Hyperproliferative diseases, such as, cancer are generally characterized by uncontrolled cellular proliferation and/or disruption in programmed cell death. Uncontrolled cellular proliferation is often caused by genetic damage to cellular pathways responsible for regulating cellular functions, such as, metabolism, cell cycle progression, cell adhesion, vascular function, apoptosis, and angiogenesis. As a result, one approach utilized in treating hyperproliferative diseases has involved targeting at least one protein involved in regulating cellular functions.
The protein kinase(s) (PK(s)) are a class of proteins that have been identified as playing an important role in regulating cellular functions. Indeed, many diseases are associated with abnormal cellular responses triggered by PK-mediated events. Such diseases include, but are not limited to, for example, autoimmune diseases, bone diseases, inflammatory diseases/disorders, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormone related diseases.
The PKs are a large and diverse group of enzymes that can be divided into groups based on the particular amino acids (serine/threonine, tyrosine, lysine, and histidine) targeted by each PK. For example, receptor and non-receptor tyrosine kinases target tyrosine, whereas cyclin dependent kinases (CDKs) and mitogen activated protein kinases (MAPKs) target both tyrosine and serine/threonine.
Exemplary PKs include, but are not limited to, receptor tyrosine kinases (RTKs); non-receptor tyrosine kinases or cellular tyrosine kinases (CTKs); serine/threonine kinases (STKs); cyclin dependent kinases (CDKs); and mitogen-activated protein kinases (MAPKs).
Exemplary RTKs include, but are not limited to, type III RTKs, such as, Flt3; “HER” RTKs, such as, epithelial growth factor receptor (EGFR), HER2, HER3, and HER4; C-MET; insulin receptor (IR); insulin-like growth factor 1 receptor (IGF-1R) and its ligands IGF-1 and IGF-2; insulin receptor related receptor (IRR); platelet derived growth factor receptors (PDGFRs), such as, PDGFRα, PDGFRβ, CSFIR, c-kit, and c-fms; fetus liver kinases (flks), such as, kinase insert domain-receptor fetal liver kinase-1 (KDR/FLK-1, VEGF-R2), flk-1R, flk-4, and fms-like tyrosine kinase 1 (flt-1); fibroblast growth factor (FGF) receptors, such as, FGFR1, FGFR2, FGFR3, and FGFR4 and FGF ligands, such as, FGF1, FGF2, FGF3, FGF4, FGF5, FGF6, and FGF7; vascular endothelial growth factor receptors (VEGFRs), such as, VEGFR1, VEGFR2, and VEGFR3; Tie receptors, such as from example, Tie2; and Trk receptors, such as, TrkA, TrkB, and TrkC. For a more detailed discussion of RTKs, see Plowman et al., KN&P, 7(6):334-339 (1994).
Exemplary CTKs include, but are not limited to, Src kinases, such as, Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, and Yrk; Frk kinases; Btk kinases; Csk kinases; Abl kinases; ZAP70 kinases; Fes kinases; Fps kinases; Fak kinases; Jak kinases; Ack kinases; and Kak kinases. For a more detailed discussion of known CTKs, see Bolen, Oncogene, 8:2025-2031 (1993).
Exemplary STKs include, but are not limited to, p90 ribosomal S6 kinases (RSKs), such as, RSK1/p90Rsk, RSK2, RSK3, and RSK4; checkpoint protein kinases, such as, CHK1 and CHK2; Aurora kinases, such as, aurora-A, aurora-B, and aurora-C; and Glycogen synthase kinase 3 (GSK3).
Exemplary CDKs include, but are not limited to, CDK1; CDK2; CDK4; CDK5; CDK6 and CDK 7; and cell division control 2 proteins (CDC2);
Exemplary MAPKs include, but are not limited to, MAPK 1 (ERK); MAPK3; MAPK7; MAPK 8 (JNK1); MAPK 14 (p38α); MAPK 10; JNK 3 a protein kinase; stress-activated protein kinase JNK 2; and MAPK 14.
In view of the link between PK-related cellular activities and a wide variety of human disorders, including, cancer, and the discovery that certain pyrrolotriazine-containing compounds exhibit inhibitory activity of at least one PK, such pyrrolotriazine-containing compounds were found to be useful in treating conditions associated with abnormal PK activity.
2,4-Dichloropyrrolo[1,2-f][1,2,4]triazine, as an intermediate for the preparation of certain pyrrolotriazine compounds, is disclosed in U.S. Ser. No. 11/426,707, filed Jun. 27, 2006. 2,4-Disubstituted pyrrolotriazine compounds are disclosed in, for example, the following provisional patent applications, U.S. Ser. No. 11/773,466, U.S. Ser. No. 11/835,456, U.S. Ser. No. 11/835,469, and PCT/US2007/083436.